Sarmentosin promotes USP17 and regulates Nrf2-mediated mitophagy and cellular oxidative stress to alleviate APAP-induced acute liver failure

Background: An overdose of acetaminophen (APAP), the main cause of acute liver failure (ALF), induces oxidative stress that ultimately causes mitochondrial impairment and hepatotoxicity. The nuclear factor erythroid 2-related factor 2 (Nrf2) was widely recognized as an anti-oxidative stress mechanism. The present study was aimed at investigating whether sarmentosin, extract from traditional Chinese medicine, protects the liver against APAP-induced injury via activating Nrf2 and subsequently decreasing oxidative stress.

Methods: Male ICR mice were treated with sarmentosin oral administration for 1 week and injected APAP (300 mg/kg. i.p.) for acute liver injury model. The liver and serum of mice for histological and biochemistry analysis. AML12 and LO2 cells were used in vitro assays.

Results: We found that sarmentosin moderately increased accumulation of Nrf2 via upregulating USP17-mediated ubiquitin inhibition at the early stage of hepatocytes damage. The Nrf2 separating from bonding protein Keap1 translocated into nucleus and activated downstream gene of Antioxidants. Mitophagy, a unique Autophagy can remove Reactive Oxygen Species (ROS) damaged mitochondria, was elevated in this progress to maintain mitochondria function and ROS homeostasis.

Conclusion: In summary, our research revealed that sarmentosin could alleviate APAP-induced liver acute injury through USP17-mediated Nrf2 overexpression and PINK1-dependent Mitophagy.

Acute liver failure; Mitophagy; Nrf2; Sarmentosin; USP17.